Alzheimer's disease (AD) affects more than 4 million Americans, is a major impediment to healthy aging, and is the most common cause of dementia in the elderly. In this competing continuation we will focus on understanding the molecular interactions between the well-defined galanin (GAL) plasticity response seen in Alzheimer's disease, the role that amyloid pathology plays in the initiation of this action and the novel finding that GAL attenuates neuronal amyloid toxicity. Overall, the data presented in this application suggest that amyloid dependent GAL over expression is an endogenous auto neuroprotective mechanism by the brain to minimize amyloid induced toxicity in Alzheimer's disease. Although evidence suggests that GAL has neuroprotective effects in response to brain damage, its response to amyloid is poorly understood. We present for the first time data demonstrating in a well characterized mouse model of AD (APPswe/PSlAE9 mice) that amyloid deposition induces hippocampal GAL hypertrophic neurites;that a loss of GAL fiber innervation in the hippocampus results in an increase in hippocampal amyloid load;that greater Afi (1-42) induced cell death is observed in hippocampal organotypic cultures from GAL knock-out (KO) as compared to wild type (WT) mice;GAL is neuroprotective against Afi(1-42) induced toxicity in hippocampal cultures derived from wild-type mice and GAL over-expressing mice (see Preliminary data). These finding support the hypothesis that amyloid triggers GAL plasticity, that GAL alters amyloid plaque deposition and protects against amyloid neurotoxicity. This application tests the following hypotheses: 1 .Amyloid increases GAL fiber hypertrophy;2. Loss of GAL innervation increases hippocampal amyloid load;and 3. Manipulation of the levels of endogenous GAL, modulates A-IS (1-42) induced hippocampal cell death. The APPswe/PS1AE9 and GAL over-expressing transgenic mice will be crossed and the hippocampal/cortical amyloid phenotype examined. The proposed investigations are timely as anti-amyloidogenic agents are being developed for Alzheimer's disease. The development of novel pharmacologic therapeutics based directly upon the pathogenics of Alzheimer's disease meet a major unmet need in the field of Alzheimer's disease. The proposed studies will provide new insights into the mechanisms underlying GAL plasticity, GAL role in the attenuation of amyloid toxicity and suggest novel therapeutic targets (e.g., GAL ligands) for the reduction of amyloid toxicity in Alzheimer's disease.